Chronic HBV infection progresses through distinct phases that are described as immune-tolerant, immune-active and immune-silent and differ in disease severity. The causative factors are not known. To allow a broad analysis of innate and adaptive immune responses we studied the transcriptome of blood mononuclear cells of HBV-infected patients that differed in HBeAg status, viremia and liver enzyme levels. Differentially expressed genes included interferon-stimulated genes, and pathway analysis identified IFNA2 and IFNL1 as the most activated upstream regulators associated with HBeAg status. We are now studying subsets of immune cells and the signals that activate them. Superinfection of chronic hepatitis B with HDV, a small RNA virus that depends on HBV surface antigen to envelope its genome, severely enhances inflammatory liver injury and progression to liver cirrhosis. The adaptive and innate cellular immune response to HDV is poorly characterized and the reason for the enhanced disease pathogenesis in HBV/HCV co-infected patients remains unknown. We demonstrated (i) that HDV induced CXCL9 and CXL10 chemokines in a type I IFN-dependent manner in an in vitro infection model, (ii) that CXCL9 and CXL10 levels were significantly higher in serum and liver of HDV/HBV co-infected patients than in HBV-mono-infected patients, and (iii) that their levels correlated with liver enzymes and histological activity score. We also have started to characterize the antigen-specificity and function of the T cells that are recruited by these chemokines. As part of this process, we have identified CD4 and CD8 T cell epitopes within the large HDV antigen and tested their respective MHC restriction. Based on these epitopes we are creating immunological reagents (peptide/MHC multimers) based on the. We will use these multimers to characterize the phenotype, differentiation status and effector function of HDV-specific T cells in chronic HDV infection.